Carnitor

If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in individual blisters, packaged in boxes of 90 (NDC 54482-144-07). Store at controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Tablets are manufactured for Sigma-Tau Pharmaceuticals, Inc. by Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy.

CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). Store at controlled room temperature (25°C). See USP. CARNITOR® (levocarnitine) Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701.

CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-148-01). Store at controlled room temperature (25°C). See USP. CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701.

Sigma-tau Pharmaceuticals, Inc., Gaithersburg, MD 20878. Revised: April 2015.

CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production.

Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with CARNITOR® . The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6

Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 μmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations.

Pharmacokinetics

In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® oral solution b.i.d., the maximum plasma concentration (Cmax) was about 80 μmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.

The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of CARNITOR® were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.

The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR® , calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution.

Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h.

Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9

Metabolism And Excretion

In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10

After attainment of steady state following 4 days of oral administration of CARNITOR® Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

REFERENCES

1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61.

2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.

3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577.

4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702.

5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540.

6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66.

7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill.

8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press.

9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368.

10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305-1310.

Carnitor is a brand name medication included in a group of medications called Amino acids and derivatives. For more information about Carnitor see its generic Levocarnitine

Various mild gastrointestinal complaints have been reported during the long-term administration of oral L-or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with CARNITOR® (levocarnitine) Oral Solution or CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases.

Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.

Read the entire FDA prescribing information for Carnitor (Levocarnitine Tablets, Oral Solution, Sugar-Free)

Read More »

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

General

• Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism.

• Obtain plasma carnitine concentrations prior to initiation of parenteral therapy.1

• Perform weekly and monthly monitoring of blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition of patient.1

• Plasma free carnitine concentrations should be 35–60 mcmol/L.1

• End-stage Renal Disease Patients undergoing Hemodialysis

• Obtain blood levocarnitine concentrations prior to therapy to establish levocarnitine deficiency.3

• Some experts recommend evaluating clinical response at 3-month intervals following initiation of drug, considering dosage adjustment to lowest effective dosage once desired outcome for specific manifestation has been attained, and discontinuing drug if clinical improvement has not occurred within 9–12 months.7

Administration

Administer orally (as a solution or tablets), by direct IV injection, or by IV infusion.1 2

Oral Administration

Solutions may be administered alone or dissolved in beverages or other liquid foods to reduce taste fatigue.2 Slowly administer solution in evenly spaced doses throughout the day (i.e., at least 3 or 4 hours apart), preferably during or following meals, to maximize tolerance; adverse GI reactions may result from rapid administration of solution.2

Periodically monitor blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition of patient.2

Closely monitor tolerance to drug during first week of administration and following any dosage increases.2

IV Administration

For solution compatibility information, see Compatibility under Stability.

Vials are for single use only.1

Rate of Administration

Secondary carnitine deficiency associated with an inborn error of metabolism, direct IV injection: Slowly over 2–3 minutes.1

Carnitine deficiency in patients with end-stage renal disease undergoing dialysis, direct IV injection: Slowly over 2–3 minutes into the venous return line after each dialysis session.1

Dosage

Decreasing the dosage of oral levocarnitine may diminish or eliminate drug-related patient body odor or GI symptoms if present.2 11

Pediatric Patients

Primary Systemic Carnitine Deficiency Oral

Pediatric patients (≤18 years of age): Initially, 50 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response.2 3 (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range is 50–100 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart), up to a maximum total daily dosage of 3 g.2 3

Exact dosage based on clinical response.2 Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.2

Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism Oral

Pediatric patients (≤18 years of age): Initially, 50 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response.2 3 (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range is 50–100 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart), up to a maximum total daily dosage of 3 g.2 3

Exact dosage depends on clinical response.2 Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.2

IV

Pediatric patients (≤18 years of age): 50 mg/kg every 3 or 4 hours administered by slow, direct IV injection over 2–3 minutes or by IV infusion; do not administer less frequently than every 6 hours.1 3 Subsequent total daily dosage of approximately 50 mg/kg, adjusted as required and given in divided doses (i.e., every 3 or 4 hours), is recommended.1

In pediatric patients (≤18 years of age) with severe metabolic crisis, a loading dose has often been administered, followed by an equivalent dose over the following 24 hours.1 3 These patients underwent close supervision and monitoring of plasma levocarnitine concentrations, with subsequent dosage adjusted accordingly.3 In individual case reports, highest total daily dosage administered has been 300 mg/kg.1 3

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis IV

Pediatric patients (≤18 years of age): Initially, 10–20 mg/kg (preferably 10 mg/kg) of dry body weight administered by slow, direct IV injection over 2–3 minutes into the venous return line after each dialysis session.1 3

Initiation of therapy may be prompted by trough (i.e., predialysis) plasma levocarnitine concentrations that are below normal (40–50 mcmol/L).1

Adjust dosage based on trough (i.e., predialysis) plasma levocarnitine concentrations; dosage reductions (e.g., to 5 mg/kg after dialysis) may be initiated as early as the third or fourth week of therapy.1 3

Adults

Primary Systemic Carnitine Deficiency Therapy with Levocarnitine Tablets Oral

990 mg 2 or 3 times daily, depending on clinical response.2

Therapy with Levocarnitine Oral Solution Oral

Initially, 1 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response.2 3 (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range for a 50-kg patient is 1–3 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart).2 3

Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.2

Secondary Carnitine Deficiency Resulting from an Inborn Error of Metabolism Therapy with Levocarnitine Tablets Oral

990 mg 2 or 3 times daily, depending on clinical response.2

Therapy with Levocarnitine Oral Solution Oral

Initially, 1 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response.2 3 (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range for a 50-kg patient is 1–3 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart).2 3

Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.2

IV

50 mg/kg every 3 or 4 hours administered by slow, direct IV injection over 2–3 minutes or by IV infusion; do not administer less frequently than every 6 hours.1 3 Subsequent total daily dosage of approximately 50 mg/kg, adjusted as required and given in divided doses (i.e., every 3 or 4 hours), is recommended.1 3

In patients with severe metabolic crisis, a loading dose often has been administered, followed by an equivalent dose during the following 24 hours.1 3 These patients underwent close supervision and monitoring of plasma levocarnitine concentrations, with subsequent dosage adjusted accordingly.3 In individual case reports, highest total daily dosage administered has been 300 mg/kg.1 3

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Diaysis IV

Initially, 10–20 mg/kg of dry body weight administered by slow, direct IV injection over 2–3 minutes into the venous return line after each dialysis session.1

Initiation of therapy may be prompted by trough (i.e., predialysis) plasma levocarnitine concentrations that are below normal (40–50 mcmol/L).1

Adjust dosage based on trough (i.e., predialysis) plasma levocarnitine concentrations; dosage reductions (e.g., to 5 mg/kg after dialysis) may be initiated as early as the third or fourth week of therapy.1

Prescribing Limits

Pediatric Patients

Primary Carnitine Deficiency Oral

Pediatric patients (≤18 years of age): In individual case reports, maximum 3 g daily.2 3

Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism Oral

Pediatric patients (≤18 years of age): In individual case reports, maximum 3 g daily.2 3

IV

Pediatric patients (≤18 years of age): In individual case reports, total daily dosage of up to 300 mg/kg has been administered.1 3

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis IV

Doses >20 mg/kg have not been shown to provide additional benefit.7 3

Adults

Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism IV

In individual case reports, total daily dosage of up to 300 mg/kg has been administered.1 3

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis IV

Doses >20 mg/kg have not been shown to provide additional benefit.7

Special Populations

No special population dosage recommendations at this time.1 2 (See Renal Impairment under Cautions.)

Contraindications

Manufacturer states none known.1 2

Warnings/Precautions

Specific Populations

Pregnancy

Category B.1 2

Lactation

Distributed into milk in cows; not known whether levocarnitine distributes into human milk.1 2 Consider discontinuance of nursing or the drug.1 2

Pediatric Use

Dosage of levocarnitine in pediatric patients ≤18 years of age was based on specific patient case record observations rather than on studies that specifically defined age by protocol.1 2 3

Renal Impairment

Safety and efficacy of oral levocarnitine not established in patients with renal impairment.1 2

Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in patients with end-stage renal disease undergoing dialysis may result in accumulation of potentially toxic metabolites, trimethylamine (TMA) and trimethyloxamine (trimethylamine-N-oxide [TMAO]), since these metabolites are normally excreted in urine.1 2 3 7

Safety of IV levocarnitine has been established in patients with end-stage renal disease.1 3

Common Adverse Effects

Oral therapy: Transient nausea and vomiting,2 abdominal cramps,2 diarrhea,2 body odor.2

Parenteral therapy: Transient nausea and vomiting,1 body odor,1 gastritis.1 Patients on chronic hemodialysis may experience injection site reactions,1 headache,1 pain,1 diarrhea,1 flu syndrome,1 pharyngitis,1 infection,1 hypertension,1 vomiting,1 abdominal pain,1 hypotension,1 dizziness,1 increased cough,1 chest pain,1 hypercalcemia,1 accidental injury,1 asthenia,1 nausea,1 fever,1 anemia,1 hypervolemia,1 paresthesia,1 rhinitis,1 or dyspnea.1

Seizures reported in patients, with or without preexisting seizure activity, receiving either oral or IV levocarnitine.1 2 12 Increased seizure frequency and/or severity also reported in patients with preexisting seizure activity.1 2

• Advise patients to drink levocarnitine oral solution alone or dissolved in beverages or other liquid foods to reduce taste fatigue.2

• Advise patients to drink levocarnitine oral solution slowly in evenly spaced doses throughout the day (at least 3 or 4 hours apart).2

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.1 2

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

• Importance of advising patients of other important precautionary information.1 2 (See Cautions.)

Do not change brands or dosage forms of levocarnitine without first checking with your doctor. Different products may not work in the same way. If you refill your medicine and it looks different, check with your pharmacist.